Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain?

Abstract

Purpose of review: Sickle cell anemia (SCA) is a well characterized severe hematological disorder with substantial morbidity and early mortality. Hydroxyurea is a potent inducer of fetal hemoglobin, and evidence over the past 25 years has documented its laboratory and clinical efficacy for both adults and children with SCA.

Recent findings: The phase III study of hydroxyurea in infants (BABY HUG) has just been completed and preliminary results indicate equivocal benefits for organ protection during the 2-year treatment period, but significant benefits for pain, acute chest syndrome, hospitalizations, and transfusions. Three new reports document the benefits of hydroxyurea on reducing mortality in SCA: two adult trials (LaSHS and MSH) and one pediatric study (Brazilian cohort). Recent results from the HUSTLE protocol suggest minimal genotoxicity or carcinogenicity with long-term hydroxyurea exposure.

Summary: The potential utility of hydroxyurea for all patients with SCA is clear and indisputable. With decades of accumulated evidence and documented efficacy with an acceptable long-term safety profile, it is time to consider hydroxyurea treatment the standard of care for all young patients with SCA. Exporting our knowledge and experience with hydroxyurea to developing nations with large medical burdens from SCA can help relieve global suffering from this condition.

Fig 1. Mechanisms of action involved in the beneficial effects of hydroxyurea for sickle cell anemia (20)

Legend: (1) Induction of fetal hemoglobin in erythroid compartment; (2) Marrow cytoxicity and decreased neutrophil and reticulocyte counts; (3) Altered expression of adhesion molecules on circulating neutrophils and reticulocytes decreases adhesiveness and subsequent endothelial damage; (4) Macrocytosis and increased hydration reduces hemolysis and intracellular sickling; (5) Local release of nitric oxide (NO) results in vasodilation. Source: Reference

Fig 2. Hydroxyurea improves survival across SCD phenotypes (40)

Legend: (A) Patients with HbS/β⁰ thalassemia and hydroxyurea exposure had improved 10-year overall survival (OS) compared to patients without hydroxyurea exposure (87% vs. 54%, p=0.001); (B) HbSS patients receiving hydroxyurea had a 10-year OS of 100% compared to 10% in those without hydroxyurea exposure (p<0.01). Source: Reference